A total of 1,108 migraine-associated genes were identified in the cortex, with 586 in the trigeminal ganglion, including 109 overlapping genes.
Overlapping genes link pathways related to and neuroinflammation, indicating shared mechanisms in migraine.
Five hub genes—HSP90AB1, EGFR, ERBB3, MET, and ATG7—are implicated in both trigeminal ganglion and cortical tissues.
ATG7 is highlighted as a key candidate gene, showing significant expression in cortical astrocytes and neurons.
In a migraine model, protein levels of LC3-II increased while LC3-I and p62 levels decreased, suggesting changes in autophagic activity.
Elevated ratios of LC3-II/LC3-I and LC3-II/p62 in the migraine model indicate active autophagic flux.
Simplified
BACKGROUND: Migraine is a complex neurological disorder with poorly understood molecular mechanisms. Despite advances in genetic and omics research, the shared mechanisms between central and peripheral nervous systems in migraine pathogenesis remain unclear.
METHODS: We employed a multi-omics approach, integrating human trigeminal ganglion (TG) single-nucleus RNA sequencing (snRNA-seq) data and expression quantitative trait loci (eQTL) data from eight major cortical cell types. (MR) analysis was used to prioritize susceptibility genes, followed by functional enrichment, molecular network mapping, and computational drug screening. Key findings were experimentally validated in the primary sensory cortex hindlimb area brain region and TG, given their established roles in pain processing.
RESULTS: We identified 586 migraine-associated genes in TG and 1,108 in the cortex, with 109 overlapping genes. These overlapping genes converge on pathways including and neuroinflammation, suggesting shared mechanisms of central and peripheral nervous systems. Five hub genes - HSP90AB1, EGFR, ERBB3, MET and ATG7 - were implicated in both TG and cortical tissues. Experimental validation identified five hub genes strongly linked to migraine, with ATG7 emerging as a key candidate. Immunofluorescence co-localization revealed ATG7's prominent expression in both cortical astrocytes and neurons, suggesting its dual role in glial and neuronal pathways underlying migraine pathophysiology. Western blot analysis revealed that in the S1HL brain region of migraine model mice, the protein level of LC3-II showed an increasing trend, while the expressions of both LC3-I and p62 exhibited decreasing trends compared to the control group. Furthermore, both the LC3-II/LC3-I ratio and the LC3-II/p62 ratio were significantly elevated in the model group, suggesting that the upregulation of ATG7 promotes the activation of autophagic flux in the migraine model, with the autophagic flux remaining unobstructed.
CONCLUSIONS: Our study provides novel insights into migraine's central and peripheral mechanisms, highlighting cell-type-specific genetic contributions and potential therapeutic targets. The integrative framework combining snRNA-seq, eQTL, GWAS, and MR enhances the understanding of migraine biology and accelerates drug discovery, offering a pathway toward more effective treatments.
Key numbers
586
Migraine-associated genes in
Total identified genes linked to migraine in the .
1,108
Migraine-associated genes in cortex
Total identified genes linked to migraine in the cortex.
109
Overlapping migraine-associated genes
Number of genes shared between and cortex.
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Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: All data analyzed during this study have been previously published. Competing interests: The authors declare no competing interests.
